Sensorimotor dysfunction due to developmental manganese exposure is less severe in adult female than male rats and partially improved by acute methylphenidate treatment.

Epidemiological studies have reported associations between elevated manganese (Mn) exposure and poorer psychomotor performance in children. Our studies in adult male rats have established that this relationship is causal and that prolonged methylphenidate (MPH) treatment is efficacious in treating this area of dysfunction. However, it is unclear if sensitivity to these Mn deficits differs between females and males, and whether existing pharmacological therapies are efficacious in improving sensorimotor dysfunction in females. To address these questions, we used our rat model of childhood environmental Mn exposure and the Montoya staircase test to determine whether 1) there are sex differences in the lasting sensorimotor dysfunction caused by developmental Mn exposure, and 2) MPH treatment is efficacious in ameliorating the sensorimotor deficits in females. Female and male neonates were treated orally with Mn (50 mg Mn/kg/d) from postnatal day 1 to 21 and evaluated for skilled forelimb sensorimotor performance as adults. Subsequently, the efficacy of acute oral MPH treatment (doses of 0, 0.5, and 3.0 mg MPH/kg/d) was assessed in females using a within-subject MPH treatment design. Developmental postnatal Mn exposure produced lasting sensorimotor reaching and grasping deficits that were milder in females than in males. Acute MPH treatment of Mn-exposed females with the 0.5 mg/kg/d dose attenuated the reaching dysfunction without alleviating grasping dysfunction. These findings show sex-based variations in sensitivity to the sensorimotor impairment caused by developmental Mn exposure, and they are consistent with prior studies showing less vulnerability of females to Mn-induced dysfunction in other functional domains, possibly due to the protective effects of estrogen. Given our previous work showing the efficacy of MPH treatment to alleviate Mn-induced inattention, impulsiveness, and sensorimotor dysfunctions in adult male rats, they also highlight the need for further research into sex-based differences in cognitive and behavioral areas of brain function, and the efficacy of therapeutics in treating behavioral dysfunction in females. Supported by NIEHS R01ES028369.

Maternal choline supplementation lessens the behavioral dysfunction produced by developmental manganese exposure in a rodent model of ADHD.

Studies in children have reported associations between elevated manganese (Mn) exposure and ADHD-related symptoms of inattention, impulsivity/hyperactivity, and psychomotor impairment. Maternal choline supplementation (MCS) during pregnancy/lactation may hold promise as a protective strategy because it has been shown to lessen cognitive dysfunction caused by numerous early insults. Our objectives were to determine whether (1) developmental Mn exposure alters behavioral reactivity/emotion regulation, in addition to impairing learning, attention, impulse control, and sensorimotor function, and (2) MCS protects against these Mn-induced impairments. Pregnant Long-Evans rats were given standard diet, or a diet supplemented with additional choline throughout gestation and lactation (GD 3 - PND 21). Male offspring were exposed orally to 0 or 50 mg Mn/kg/day over PND 1-21. In adulthood, animals were tested in a series of learning, attention, impulse control, and sensorimotor tasks. Mn exposure caused lasting dysfunction in attention, reactivity to errors and reward omission, learning, and sensorimotor function, recapitulating the constellation of symptoms seen in ADHD children. MCS lessened Mn-induced attentional dysfunction and partially normalized reactivity to committing an error or not receiving an expected reward but provided no protection against Mn-induced learning or sensorimotor dysfunction. In the absence of Mn exposure, MCS produces lasting offspring benefits in learning, attention, and reactivity to errors. To conclude, developmental Mn exposure produces a constellation of deficits consistent with ADHD symptomology, and MCS offered some protection against the adverse Mn effects, adding to the evidence that maternal choline supplementation is neuroprotective for offspring and improves offspring cognitive functioning.

Methylphenidate alleviates cognitive dysfunction caused by early manganese exposure: Role of catecholaminergic receptors.

Environmental manganese (Mn) exposure is associated with impaired attention and psychomotor functioning, as well as impulsivity/hyperactivity in children and adolescents. We have shown previously that developmental Mn exposure can cause these same dysfunctions in a rat model. Methylphenidate (MPH) lessens impairments in attention, impulse control, and psychomotor function in children, but it is unknown whether MPH ameliorates these dysfunctions when induced by developmental Mn exposure. Here, we sought to (1) determine whether oral MPH treatment ameliorates the lasting attention and sensorimotor impairments caused by developmental Mn exposure, and (2) elucidate the mechanism(s) of Mn neurotoxicity and MPH effectiveness. Rats were given 50 mg Mn/kg/d orally over PND 1-21 and assessed as adults in a series of attention, impulse control and sensorimotor tasks during oral MPH treatment (0, 0.5, 1.5, or 3.0 mg/kg/d). Subsequently, selective catecholaminergic receptor antagonists were administered to gain insight into the mechanism(s) of action of Mn and MPH. Developmental Mn exposure caused persistent attention and sensorimotor impairments. MPH treatment at 0.5 mg/kg/d completely ameliorated the Mn attentional dysfunction, whereas the sensorimotor deficits were ameliorated by the 3.0 mg/kg/d MPH dose. Notably, the MPH benefit on attention was only apparent after prolonged treatment, while MPH efficacy for the sensorimotor deficits emerged early in treatment. Selectively antagonizing D1, D2, or α2A receptors had no effect on the Mn-induced attentional dysfunction or MPH efficacy in this domain. However, antagonism of D2R attenuated the Mn sensorimotor deficits, whereas the efficacy of MPH to ameliorate those deficits was diminished by D1R antagonism. These findings demonstrate that MPH is effective in alleviating the lasting attentional and sensorimotor dysfunction caused by developmental Mn exposure, and they clarify the mechanisms underlying developmental Mn neurotoxicity and MPH efficacy. Given that the cause of attention and psychomotor deficits in children is often unknown, these findings have implications for the treatment of environmentally induced attentional and psychomotor dysfunction in children more broadly.

Methylphenidate alleviates cognitive dysfunction from early Mn exposure: Role of catecholaminergic receptors.

Environmental manganese (Mn) exposure is associated with impaired attention and psychomotor functioning, as well as impulsivity/hyperactivity in children and adolescents. We have shown previously that developmental Mn exposure can cause these same dysfunctions in a rat model. Methylphenidate (MPH) lessens impairments in attention, impulse control, and sensorimotor function in children, but it is unknown whether MPH ameliorates these dysfunctions when induced by developmental Mn exposure. Here, we sought to (1) determine whether oral MPH treatment ameliorates the lasting attention and sensorimotor impairments caused by developmental Mn exposure, and (2) elucidate the mechanism(s) of Mn neurotoxicity and MPH effectiveness. Rats were given 50 mg Mn/kg/d orally over PND 1-21 and assessed as adults in a series of attention, impulse control and sensorimotor tasks during oral MPH treatment (0, 0.5, 1.5, or 3.0 mg/kg/d). Subsequently, selective catecholaminergic receptor antagonists were administered to gain insight into the mechanism(s) of action of Mn and MPH. Developmental Mn exposure caused persistent attention and sensorimotor impairments. MPH treatment at 0.5 mg/kg/d completely ameliorated the Mn attentional dysfunction, whereas the sensorimotor deficits were ameliorated by the 3.0 mg/kg/d MPH dose. Notably, the MPH benefit on attention was only apparent after prolonged treatment, while MPH efficacy for the sensorimotor deficits emerged early in treatment. Selectively antagonizing D1, D2, or α2A receptors had no effect on the Mn-induced attentional dysfunction or MPH efficacy in this domain. However, antagonism of D2R attenuated the Mn sensorimotor deficits, whereas the efficacy of MPH to ameliorate those deficits was diminished by D1R antagonism. These findings demonstrate that MPH is effective in alleviating the lasting attention and sensorimotor dysfunction caused by developmental Mn exposure, and they clarify the mechanisms underlying developmental Mn neurotoxicity and MPH efficacy. Given that the cause of attention and psychomotor deficits in children is often unknown, these findings have implications for the treatment of environmentally-induced attentional and psychomotor dysfunction in children more broadly.

Maternal choline supplementation lessens the behavioral dysfunction produced by developmental manganese exposure in a rodent model of ADHD.

Studies in children have reported associations between elevated manganese (Mn) exposure and ADHD-related symptoms of inattention, impulsivity/hyperactivity, and psychomotor impairment. Maternal choline supplementation (MCS) during pregnancy/lactation may hold promise as a protective strategy because it has been shown to lessen cognitive dysfunction caused by numerous early insults. Our objectives were to determine whether (1) developmental Mn exposure alters behavioral reactivity/emotion regulation, in addition to impairing learning, attention, impulse control, and sensorimotor function, and (2) MCS protects against these Mn-induced impairments. Pregnant Long-Evans rats were given standard diet, or a diet supplemented with additional choline throughout gestation and lactation (G3 - PND 21). Male offspring were exposed orally to 0 or 50 mg Mn/kg/day over PND 1-21. In adulthood, animals were tested in a series of learning, attention, impulse control, and sensorimotor tasks. Mn exposure caused lasting dysfunction in attention, reactivity to errors and reward omission, learning, and sensorimotor function, recapitulating the constellation of symptoms seen in ADHD children. MCS lessened Mn-induced attentional dysfunction and partially normalized reactivity to committing an error or not receiving an expected reward but provided no protection against Mn-induced learning or sensorimotor dysfunction. In the absence of Mn exposure, MCS produces lasting offspring benefits in learning, attention, and reactivity to errors. To conclude, developmental Mn exposure produces a constellation of deficits consistent with ADHD symptomology, and MCS offered some protection against the adverse Mn effects, adding to the evidence that maternal choline supplementation is neuroprotective for offspring and improves offspring cognitive functioning. Highlights: Developmental Mn exposure causes lasting dysfunction consistent with ADHD symptomology.Maternal choline supplementation (MCS) protects against Mn-induced deficits in attention and behavioral reactivity.MCS in control animals produces lasting benefits to offspring in learning, attention, and error reactivity.These data support efforts to increase choline intake during pregnancy, particularly for individuals at risk of neurotoxicant exposure.

Animal Models of Childhood Exposure to Lead or Manganese: Evidence for Impaired Attention, Impulse Control, and Affect Regulation and Assessment of Potential Therapies.

Behavioral disorders involving attention and impulse control dysfunction, such as ADHD, are among the most prevalent disorders in children and adolescents, with significant impact on their lives. The etiology of these disorders is not well understood, but is recognized to be multifactorial, with studies reporting associations with polygenic and environmental risk factors, including toxicant exposure. Environmental epidemiological studies, while good at establishing associations with a variety of environmental and genetic risk factors, cannot establish causality. Animal models of behavioral disorders, when properly designed, can play an essential role in establishing causal relationships between environmental risk factors and a disorder, as well as provide model systems for elucidating underlying neural mechanisms and testing therapies. Here, we review how animal model studies of developmental lead or manganese exposure have been pivotal in (1) establishing a causal relationship between developmental exposure and lasting dysfunction in the domains of attention, impulse control, and affect regulation, and (2) testing the efficacy of specific therapeutic approaches for alleviating the lasting deficits. The lead and manganese case studies illustrate how animal models can advance knowledge in ways that are not possible in human studies. For example, in contrast to the Treatment of Lead Poisoned Children (TLC) human clinical trial evaluating succimer chelation efficacy to improve cognitive functioning in lead-exposed children, our developmental lead exposure animal model showed that succimer chelation can produce lasting cognitive benefits if chelation sufficiently reduces brain lead levels. In addition, this study revealed that succimer treatment in the absence of lead exposure produces lasting cognitive dysfunction, highlighting potential risks of chelation in off-label uses, such as the treatment of autistic children without a history of lead exposure. Our animal model of developmental manganese exposure has demonstrated that manganese can cause lasting attentional and sensorimotor deficits, akin to an ADHD-inattentive behavioral phenotype, thereby providing insights into the role of environmental exposures as contributors to ADHD. These studies have also shown that oral methylphenidate (Ritalin) can fully alleviate the deficits produced by early developmental Mn exposure. Future work should continue to focus on the development and use of animal models that appropriately recapitulate the complex behavioral phenotypes of behavioral disorders, in order to determine the mechanistic basis for the behavioral deficits caused by developmental exposure to environmental toxicants, and the efficacy of existing and emerging therapies.

Prenatal choline supplementation improves child sustained attention: A 7-year follow-up of a randomized controlled feeding trial.

Numerous rodent studies demonstrate developmental programming of offspring cognition by maternal choline intake, with prenatal choline deprivation causing lasting adverse effects and supplemental choline producing lasting benefits. Few human studies have evaluated the effect of maternal choline supplementation on offspring cognition, with none following children to school age. Here, we report results from a controlled feeding study in which pregnant women were randomized to consume 480 mg choline/d (approximately the Adequate Intake [AI]) or 930 mg choline/d during the 3rd trimester. Sustained attention was assessed in the offspring at age 7 years (n = 20) using a signal detection task that showed benefits of maternal choline supplementation in a murine model. Children in the 930 mg/d group showed superior performance (vs. 480 mg/d group) on the primary endpoint (SAT score, p = .02) and a superior ability to maintain correct signal detections (hits) across the 12-min session (p = .02), indicative of improved sustained attention. This group difference in vigilance decrement varied by signal duration (p = .04). For the briefest (17 ms) signals, the 480 mg/d group showed a 22.9% decline in hits across the session compared to a 1.5% increase in hits for the 930 mg/d group (p = .04). The groups did not differ in vigilance decrement for 29 or 50 ms signals. This pattern suggests an enhanced ability to sustain perceptual amplification of a brief low-contrast visual signal by children in the 930 mg/d group. This inference of improved sustained attention by the 930 mg/d group is strengthened by the absence of group differences for false alarms, omissions, and off-task behaviors. This pattern of results indicates that maternal 3rd trimester consumption of the choline AI for pregnancy (vs. double the AI) produces offspring with a poorer ability to sustain attention-reinforcing concerns that, on average, choline consumption by pregnant women is approximately 70% of the AI.

Maternal Choline Supplementation as a Potential Therapy for Down Syndrome: Assessment of Effects Throughout the Lifespan.

Maternal choline supplementation (MCS) has emerged as a promising therapy to lessen the cognitive and affective dysfunction associated with Down syndrome (DS). Choline is an essential nutrient, especially important during pregnancy due to its wide-ranging ontogenetic roles. Using the Ts65Dn mouse model of DS, our group has demonstrated that supplementing the maternal diet with additional choline (4-5 × standard levels) during pregnancy and lactation improves spatial cognition, attention, and emotion regulation in the adult offspring. The behavioral benefits were associated with a rescue of septohippocampal circuit atrophy. These results have been replicated across a series of independent studies, although the magnitude of the cognitive benefit has varied. We hypothesized that this was due, at least in part, to differences in the age of the subjects at the time of testing. Here, we present new data that compares the effects of MCS on the attentional function of adult Ts65Dn offspring, which began testing at two different ages (6 vs. 12 months of age). These data replicate and extend the results of our previous reports, showing a clear pattern indicating that MCS has beneficial effects in Ts65Dn offspring throughout life, but that the magnitude of the benefit (relative to non-supplemented offspring) diminishes with aging, possibly because of the onset of Alzheimer's disease-like neuropathology. In light of growing evidence that increased maternal choline intake during pregnancy is beneficial to the cognitive and affective functioning of all offspring (e.g., neurotypical and DS), the addition of this nutrient to a prenatal vitamin regimen would be predicted to have population-wide benefits and provide early intervention for fetuses with DS, notably including babies born to mothers unaware that they are carrying a fetus with DS.

Early Postnatal Manganese Exposure Reduces Rat Cortical and Striatal Biogenic Amine Activity in Adulthood.

Growing evidence from studies with children and animal models suggests that elevated levels of manganese during early development lead to lasting cognitive and fine motor deficits. This study was performed to assess presynaptic biogenic amine function in forebrain of adult Long-Evans rats exposed orally to 0, 25, or 50 mg Mn/kg/day over postnatal day 1-21 or continuously from birth to the end of the study (approximately postnatal day 500). Intracerebral microdialysis in awake rats quantified evoked outflow of biogenic amines in the right medial prefrontal cortex and left striatum. Results indicated that brain manganese levels in the early life exposed groups (postnatal day 24) largely returned to control levels by postnatal day 66, whereas levels in the lifelong exposed groups remained elevated 10%-20% compared with controls at the same ages. Manganese exposure restricted to the early postnatal period caused lasting reductions in cortical potassium-stimulated extracellular norepinephrine, dopamine, and serotonin, and reductions in striatal extracellular dopamine. Lifelong manganese exposure produced similar effects with the addition of significant decreases in cortical dopamine that were not evident in the early postnatal exposed groups. These results indicate that early postnatal manganese exposure produces persistent deficits in cortical and striatal biogenic amine function. Given that these same animals exhibited lasting impairments in attention and fine motor function, these findings suggest that reductions in catecholaminergic activity are a primary factor underlying the behavioral effects caused by manganese, and indicate that children exposed to elevated levels of manganese during early development are at the greatest risk for neuronal deficiencies that persist into adulthood.

Early postnatal manganese exposure causes arousal dysregulation and lasting hypofunctioning of the prefrontal cortex catecholaminergic systems.

Studies have reported associations between environmental manganese (Mn) exposure and impaired cognition, attention, impulse control, and fine motor function in children. Our recent rodent studies established that elevated Mn exposure causes these impairments. Here, rats were exposed orally to 0, 25, or 50 mg Mn kg-1  day-1 during early postnatal life (PND 1-21) or lifelong to determine whether early life Mn exposure causes heightened behavioral reactivity in the open field, lasting changes in the catecholaminergic systems in the medial prefrontal cortex (mPFC), altered dendritic spine density, and whether lifelong exposure exacerbates these effects. We also assessed astrocyte reactivity (glial fibrillary acidic protein, GFAP), and astrocyte complement C3 and S100A10 protein levels as markers of A1 proinflammatory or A2 anti-inflammatory reactive astrocytes. Postnatal Mn exposure caused heightened behavioral reactivity during the first 5-10 min intervals of daily open field test sessions, consistent with impairments in arousal regulation. Mn exposure reduced the evoked release of norepinephrine (NE) and caused decreased protein levels of tyrosine hydroxylase (TH), dopamine (DA) and NE transporters, and DA D1 receptors, along with increased DA D2 receptors. Mn also caused a lasting increase in reactive astrocytes (GFAP) exhibiting increased A1 and A2 phenotypes, with a greater induction of the A1 proinflammatory phenotype. These results demonstrate that early life Mn exposure causes broad lasting hypofunctioning of the mPFC catecholaminergic systems, consistent with the impaired arousal regulation, attention, impulse control, and fine motor function reported in these animals, suggesting that mPFC catecholaminergic dysfunction may underlie similar impairments reported in Mn-exposed children.

Long-term effects of maternal choline supplementation on CA1 pyramidal neuron gene expression in the Ts65Dn mouse model of Down syndrome and Alzheimer's disease.

Choline is critical for normative function of 3 major pathways in the brain, including acetylcholine biosynthesis, being a key mediator of epigenetic regulation, and serving as the primary substrate for the phosphatidylethanolamine N-methyltransferase pathway. Sufficient intake of dietary choline is critical for proper brain function and neurodevelopment. This is especially important for brain development during the perinatal period. Current dietary recommendations for choline intake were undertaken without critical evaluation of maternal choline levels. As such, recommended levels may be insufficient for both mother and fetus. Herein, we examined the impact of perinatal maternal choline supplementation (MCS) in a mouse model of Down syndrome and Alzheimer's disease, the Ts65Dn mouse relative to normal disomic littermates, to examine the effects on gene expression within adult offspring at ∼6 and 11 mo of age. We found MCS produces significant changes in offspring gene expression levels that supersede age-related and genotypic gene expression changes. Alterations due to MCS impact every gene ontology category queried, including GABAergic neurotransmission, the endosomal-lysosomal pathway and autophagy, and neurotrophins, highlighting the importance of proper choline intake during the perinatal period, especially when the fetus is known to have a neurodevelopmental disorder such as trisomy.-Alldred, M. J., Chao, H. M., Lee, S. H., Beilin, J., Powers, B. E., Petkova, E., Strupp, B. J., Ginsberg, S. D. Long-term effects of maternal choline supplementation on CA1 pyramidal neuron gene expression in the Ts65Dn mouse model of Down syndrome and Alzheimer's disease.

Maternal Choline Supplementation Alters Basal Forebrain Cholinergic Neuron Gene Expression in the Ts65Dn Mouse Model of Down Syndrome.

Down syndrome (DS), trisomy 21, is marked by intellectual disability and a premature aging profile including degeneration of the basal forebrain cholinergic neuron (BFCN) projection system, similar to Alzheimer's disease (AD). Although data indicate that perinatal maternal choline supplementation (MCS) alters the structure and function of these neurons in the Ts65Dn mouse model of DS and AD (Ts), whether MCS affects the molecular profile of vulnerable BFCNs remains unknown. We investigated the genetic signature of BFCNs obtained from Ts and disomic (2N) offspring of Ts65Dn dams maintained on a MCS diet (Ts+, 2N+) or a choline normal diet (ND) from mating until weaning, then maintained on ND until 4.4-7.5 months of age. Brains were then collected and prepared for choline acetyltransferase (ChAT) immunohistochemistry and laser capture microdissection followed by RNA extraction and custom-designed microarray analysis. Findings revealed upregulation of select transcripts in classes of genes related to the cytoskeleton (Tubb4b), AD (Cav1), cell death (Bcl2), presynaptic (Syngr1), immediate early (Fosb, Arc), G protein signaling (Gabarap, Rgs10), and cholinergic neurotransmission (Chrnb3) in Ts compared to 2N mice, which were normalized with MCS. Moreover, significant downregulation was seen in select transcripts associated with the cytoskeleton (Dync1h1), intracellular signaling (Itpka, Gng3, and Mlst8), and cell death (Ccng1) in Ts compared to 2N mice that was normalized with MCS. This study provides insight into genotype-dependent differences and the effects of MCS at the molecular level within a key vulnerable cell type in DS and AD.

Rapid forgetting of social learning in the Ts65Dn mouse model of Down syndrome: New evidence for hippocampal dysfunction.

The Ts65Dn mouse model of Down syndrome recapitulates the hallmark areas of dysfunction that characterize the human disorder, including impaired performance in tasks designed to tap hippocampus-dependent learning and memory. Unfortunately, performance in the water maze tasks most commonly used for this purpose can be affected by behavioral and/or physiological abnormalities characteristic of Ts65Dn mice (e.g., thigmotaxis, susceptibility to hypothermia, stress reactivity), which complicates interpretation of impaired performance. The current study assessed hippocampal function in Ts65Dn mice using the social transmission of food preference (STFP) paradigm, which does not entail water escape or aversive reinforcement, and thus avoids these interpretive confounds. We tested Ts65Dn mice and disomic controls on this task using 1- and 7-day retention intervals. The Ts65Dn mice exhibited normal learning and memory following the 1-day retention interval, but rapid forgetting of the socially acquired information, evidenced by impaired performance following the 7-day retention interval. The STFP paradigm can be a valuable tool for studies using the Ts65Dn mouse model to evaluate potential therapies that may ameliorate hippocampal dysfunction and aging-related cognitive decline in Down syndrome. (PsycINFO Database Record

CA1 pyramidal neuron gene expression mosaics in the Ts65Dn murine model of Down syndrome and Alzheimer's disease following maternal choline supplementation.

Although there are changes in gene expression and alterations in neuronal density and afferent inputs in the forebrain of trisomic mouse models of Down syndrome (DS) and Alzheimer's disease (AD), there is a lack of systematic assessments of gene expression and encoded proteins within individual vulnerable cell populations, precluding translational investigations at the molecular and cellular level. Further, no effective treatment exists to combat intellectual disability and basal forebrain cholinergic neurodegeneration seen in DS. To further our understanding of gene expression changes before and following cholinergic degeneration in a well-established mouse model of DS/AD, the Ts65Dn mouse, we assessed RNA expression levels from CA1 pyramidal neurons at two adult ages (∼6 months of age and ∼11 months of age) in both Ts65Dn and their normal disomic (2N) littermates. We further examined a therapeutic intervention, maternal choline supplementation (MCS), which has been previously shown to lessen dysfunction in spatial cognition and attention, and have protective effects on the survival of basal forebrain cholinergic neurons in the Ts65Dn mouse model. Results indicate that MCS normalized expression of several genes in key gene ontology categories, including synaptic plasticity, calcium signaling, and AD-associated neurodegeneration related to amyloid-beta peptide (Aß) clearance. Specifically, normalized expression levels were found for endothelin converting enzyme-2 (Ece2), insulin degrading enzyme (Ide), Dyrk1a, and calcium/calmodulin-dependent protein kinase II (Camk2a), among other relevant genes. Single population expression profiling of vulnerable CA1 pyramidal neurons indicates that MCS is a viable therapeutic for long-term reprogramming of key transcripts involved in neuronal signaling that are dysregulated in the trisomic mouse brain which have translational potential for DS and AD.

Maternal choline supplementation during the third trimester of pregnancy improves infant information processing speed: a randomized, double-blind, controlled feeding study.

Rodent studies demonstrate that supplementing the maternal diet with choline during pregnancy produces life-long cognitive benefits for the offspring. In contrast, the two experimental studies examining cognitive effects of maternal choline supplementation in humans produced inconsistent results, perhaps because of poor participant adherence and/or uncontrolled variation in intake of choline or other nutrients. We examined the effects of maternal choline supplementation during pregnancy on infant cognition, with intake of choline and other nutrients tightly controlled. Women entering their third trimester were randomized to consume, until delivery, either 480 mg choline/d ( n = 13) or 930 mg choline/d ( n = 13). Infant information processing speed and visuospatial memory were tested at 4, 7, 10, and 13 mo of age ( n = 24). Mean reaction time averaged across the four ages was significantly faster for infants born to mothers in the 930 ( vs. 480) mg choline/d group. This result indicates that maternal consumption of approximately twice the recommended amount of choline during the last trimester improves infant information processing speed. Furthermore, for the 480-mg choline/d group, there was a significant linear effect of exposure duration (infants exposed longer showed faster reaction times), suggesting that even modest increases in maternal choline intake during pregnancy may produce cognitive benefits for offspring.-Caudill, M. A., Strupp, B. J., Muscalu, L., Nevins, J. E. H., Canfield, R. L. Maternal choline supplementation during the third trimester of pregnancy improves infant information processing speed: a randomized, double-blind, controlled feeding study.

Methylphenidate alleviates manganese-induced impulsivity but not distractibility.

Recent studies from our lab have demonstrated that postnatal manganese (Mn) exposure in a rodent model can cause lasting impairments in fine motor control and attention, and that oral methylphenidate (MPH) treatment can effectively treat the dysfunction in fine motor control. However, it is unknown whether MPH treatment can alleviate the impairments in attention produced by Mn exposure. Here we used a rodent model of postnatal Mn exposure to determine whether (1) oral MPH alleviates attention and impulse control deficits caused by postnatal Mn exposure, using attention tasks that are variants of the 5-choice serial reaction time task, and (2) whether these treatments affected neuronal dendritic spine density in the medial prefrontal cortex (mPFC) and dorsal striatum. Male Long-Evans rats were exposed orally to 0 or 50Mn/kg/d throughout life starting on PND 1, and tested as young adults (PND 107-115) on an attention task that specifically tapped selective attention and impulse control. Animals were treated with oral MPH (2.5mg/kg/d) throughout testing on the attention task. Our findings show that lifelong postnatal Mn exposure impaired impulse control and selective attention in young adulthood, and that a therapeutically relevant oral MPH regimen alleviated the Mn-induced dysfunction in impulse control, but not selective attention, and actually impaired focused attention in the Mn group. In addition, the effect of MPH was qualitatively different for the Mn-exposed versus control animals across a range of behavioral measures of inhibitory control and attention, as well as dendritic spine density in the mPFC, suggesting that postnatal Mn exposure alters catecholaminergic systems modulating these behaviors. Collectively these findings suggest that MPH may hold promise for treating the behavioral dysfunction caused by developmental Mn exposure, although further research is needed with multiple MPH doses to determine whether a dose can be identified that ameliorates the dysfunction in both impulse control and selective attention, without impairing focused attention.

Early Postnatal Manganese Exposure Causes Lasting Impairment of Selective and Focused Attention and Arousal Regulation in Adult Rats.

BACKGROUND: Studies in children and adolescents have associated early developmental manganese (Mn) exposure with inattention, impulsivity, hyperactivity, and oppositional behaviors, but causal inferences are precluded by the correlational nature of the data and generally limited control for potential confounders. OBJECTIVES: To determine whether early postnatal oral Mn exposure causes lasting attentional and impulse control deficits in adulthood, and whether continued lifelong Mn exposure exacerbates these effects, using a rat model of environmental Mn exposure. METHODS: Neonates were exposed orally to 0, 25 or 50 mg Mn/kg/day during early postnatal life (PND 1-21) or throughout life from PND 1 until the end of the study. In adulthood, the animals were tested on a series of learning and attention tasks using the five-choice serial reaction time task. RESULTS: Early postnatal Mn exposure caused lasting attentional dysfunction due to impairments in attentional preparedness, selective attention, and arousal regulation, whereas associative ability (learning) and impulse control were spared. The presence and severity of these deficits varied with the dose and duration of Mn exposure. CONCLUSIONS: This study is the first to show that developmental Mn exposure can cause lasting impairments in focused and selective attention and arousal regulation, and to identify the specific nature of the impairments. Given the importance of attention and arousal regulation in cognitive functioning, these findings substantiate concerns about the adverse effects of developmental Mn exposure in humans. Citation: Beaudin SA, Strupp BJ, Strawderman M, Smith DR. 2017. Early postnatal manganese exposure causes lasting impairment of selective and focused attention and arousal regulation in adult rats. Environ Health Perspect 125:230-237; http://dx.doi.org/10.1289/EHP258.

Maternal choline supplementation in a mouse model of Down syndrome: Effects on attention and nucleus basalis/substantia innominata neuron morphology in adult offspring.

The Ts65Dn mouse model of Down syndrome (DS) and Alzheimer's disease (AD) exhibits cognitive impairment and degeneration of basal forebrain cholinergic neurons (BFCNs). Our prior studies demonstrated that maternal choline supplementation (MCS) improves attention and spatial cognition in Ts65Dn offspring, normalizes hippocampal neurogenesis, and lessens BFCN degeneration in the medial septal nucleus (MSN). Here we determined whether (i) BFCN degeneration contributes to attentional dysfunction, and (ii) whether the attentional benefits of perinatal MCS are due to changes in BFCN morphology. Ts65Dn dams were fed either a choline-supplemented or standard diet during pregnancy and lactation. Ts65Dn and disomic (2N) control offspring were tested as adults (12-17months of age) on a series of operant attention tasks, followed by morphometric assessment of BFCNs. Ts65Dn mice demonstrated impaired learning and attention relative to 2N mice, and MCS significantly improved these functions in both genotypes. We also found, for the first time, that the number of BFCNs in the nucleus basalis of Meynert/substantia innominata (NBM/SI) was significantly increased in Ts65Dn mice relative to controls. In contrast, the number of BFCNs in the MSN was significantly decreased. Another novel finding was that the volume of BFCNs in both basal forebrain regions was significantly larger in Ts65Dn mice. MCS did not normalize any of these morphological abnormalities in the NBM/SI or MSN. Finally, correlational analysis revealed that attentional performance was inversely associated with BFCN volume, and positively associated with BFCN density. These results support the lifelong attentional benefits of MCS for Ts65Dn and 2N offspring and have profound implications for translation to human DS and pathology attenuation in AD.

Vitamin B-12 and Cognition in Children.

Vitamin B-12 is essential for brain development, neural myelination, and cognitive function. Inadequate vitamin B-12 status during pregnancy and early childhood has been associated with adverse child health outcomes, including impaired cognitive development. However, the underlying mechanisms have not been elucidated. This review was conducted to examine the evidence that links vitamin B-12 and cognition in children. The search strategy resulted in 17 studies: 3 cross-sectional, 1 case-control, and 12 cohort studies, and 1 randomized trial. Cognitive processes assessed included attention, memory, and perception. Developmental outcomes, academic performance, and intelligence quotient were also considered. Despite the high prevalence of vitamin B-12 insufficiency and associated risk of adverse cognitive outcomes in children, to our knowledge, no studies to date have been conducted to examine the effects of vitamin B-12 supplementation on cognition in children. The role of vitamin B-12 in the etiology of child cognitive outcomes needs to be elucidated to inform public health interventions.

Attentional function and basal forebrain cholinergic neuron morphology during aging in the Ts65Dn mouse model of Down syndrome.

Individuals with Down syndrome (DS) exhibit intellectual disability and develop Alzheimer's disease-like neuropathology during the third decade of life. The Ts65Dn mouse model of DS exhibits key features of both disorders, including impairments in learning, attention and memory, as well as atrophy of basal forebrain cholinergic neurons (BFCNs). The present study evaluated attentional function in relation to BFCN morphology in young (3 months) and middle-aged (12 months) Ts65Dn mice and disomic (2N) controls. Ts65Dn mice exhibited attentional dysfunction at both ages, with greater impairment in older trisomics. Density of BFCNs was significantly lower for Ts65Dn mice independent of age, which may contribute to attentional dysfunction since BFCN density was positively associated with performance on an attention task. BFCN volume decreased with age in 2N but not Ts65Dn mice. Paradoxically, BFCN volume was greater in older trisomic mice, suggestive of a compensatory response. In sum, attentional dysfunction occurred in both young and middle-aged Ts65Dn mice, which may in part reflect reduced density and/or phenotypic alterations in BFCNs.